TnC and Anti-TnC Antibodies
Tenascins are a highly conserved family of large multimeric extracellular matrix (ECM) glycoproteins, which is found in vertebrates. Four tenascin paralogues have been identified in mammals, termed Tenascin-C (TnC), tenascin-R, tenascin-X and tenascin-W. Tenascin family proteins have a common primary structure, comprising N-terminal heptad repeats, epidermal growth factor (EGF)-like repeats, fibronectin type III domain repeats and a C-terminal fibrinogen-like globular domain. Via an N-terminal oligomerization domain, individual subunits assemble into trimers or, as is the case for Tenascin-C, even hexamers.
Mammalian TnC monomers typically have 14.5 EGF-like repeats and 8 fibronectin type III domain repeats that are shared by all TnC isoforms. However, up to 9 additional fibronectin type III domain repeats (domains A1 to D) can be independently included or excluded by alternative splicing, giving rise to a large number of TnC isoforms (see e.g., Hsia and Schwarzbauer, J Biol Chem 280, 26641-26644 (2005)).
TnC is transiently expressed in the developing embryo, but virtually absent from adult tissues. It reappears, however, in tissues undergoing remodeling processes, including certain pathological conditions such as wound healing, inflammation and cancer (reviewed in Chiquet-Ehrismann & Chiquet, J Pathol 200, 488-499 (2003)).
Importantly, TnC is highly expressed in the majority of malignant solid tumors, including tumors of the brain, breast, colon, lung, skin and other organs (reviewed in Orend and Chiquet-Ehrismann, Cancer Letters 244, 143-163 (2006)), where it may be expressed by transformed epithelial cells as well as stromal cells in the tumor microenvironment (Yoshida et al., J Pathol 182, 421-428 (1997), Hanamura et al., Int J Cancer 73, 10-15 (1997)). In particular, the “large isoform” of TnC, containing the alternatively spliced domains A1 to D, is expressed in invasive carcinomas while being nearly undetectable in healthy adult tissues (Borsi et al., Int J Cancer 52, 688-692 (1992), Carnemolla et al., Eur J Biochem 205, 561-567 (1992)).
Its expression pattern makes TnC, in particular its alternatively spliced domains, a promising antigen for tumor targeting applications, and accordingly a number of antibodies against several domains of the protein have been developed (see e.g., Brack et al., Clin Cancer Res 12, 3200-3208 (2006) or EP 1 817 345, describing antibodies against the A1 domain of TnC; Silacci et al., Prot Eng Des Sel 19, 471-478 (2006), or EP 1 173 766, describing antibodies against the C domain of TnC; Wang et al., Hybridoma 29, 13-16 (2010), describing an antibody against the D domain of TnC; or Balza et al., FEBS 332, 39-43 (1993), describing several antibodies against different domains of human tenascin). Recently, also antibodies recognizing a specific epitope in the A2 domain of human TnC has been described (WO 2009/089998 and WO 2012/020038).
Still, there remains a need for tenascin antibodies with improved therapeutic potential for human therapy. Specifically targeting tenascin isoforms with high affinity and cross-species reactivity is much needed for improved cancer therapy, including, but not limited to, humans.